Carcinogenic effects of exogenous and endogenous glucagon-like peptide-2 in azoxymethane-treated mice.

Glucagon-like peptide-2 (GLP-2) is a nutrient-dependent intestinotropic hormone that promotes intestinal growth, via increased intestinal proliferation and decreased apoptosis, as well as increases in nutrient absorption and barrier function. The long-acting analog h(Gly(2))GLP-2[1-33] is currently being tested for treatment of short bowel syndrome and Crohn's disease. However, the role of GLP-2 in colon carcinogenesis is controversial. To assess the intestinotropic effects of exogenous and endogenous GLP-2, C57BL6/J mice were injected with 1 microg h(Gly(2))GLP-2[1-33]; 30 or 60 ng hGLP-2[3-33], a GLP-2 receptor antagonist; or PBS (4 wk, twice a day, sc). Chronic h(Gly(2))GLP-2[1-33] increased small intestinal weight/body weight (P < 0.001), villus height (P < 0.001), crypt depth (P < 0.001), and crypt cell proliferation, as measured by expression of the proliferative marker Ki67 (P < 0.05-0.01). In contrast, chronic hGLP-2[3-33] decreased small intestinal weight/body weight (P < 0.05) and colon weight/body weight (P < 0.05). To assess the carcinogenic effects of endogenous and exogenous GLP-2, separate mice were injected with azoxymethane (10 mg/kg, 4 wk, every 7 d, ip), followed by 1.5 microg h(Gly(2))GLP-2[1-33], 30 ng hGLP-2[3-33], or PBS (4 wk, twice a day, sc) 2 or 12 wk thereafter. At 10 or 46 wk after azoxymethane treatment, the numbers of aberrant crypt foci increased with h(Gly(2))GLP-2[1-33] (P < 0.001) and decreased with hGLP-2[3-33] (P < 0.01-0.05) treatment. Furthermore, mucin-depleted aberrant foci, consistent with progressive dysplasia, were almost exclusively present in h(Gly(2))GLP-2[1-33]-treated mice (P < 0.01-0.001). Additionally, adenocarcinomas developed in h(Gly(2))GLP-2[1-33]-treated mice but not in those receiving hGLP-2[3-33] or PBS. Taken together, these studies indicate that chronic treatment with GLP-2 enhances colon carcinogenesis, whereas antagonism of the GLP-2 receptor decreases dysplasia, with possible implications for human therapy.

Dietary folate deficiency suppresses N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats.

Epidemiologic studies have suggested that dietary folate intake is inversely related to breast cancer risk. However, epidemiologic evidence has not been consistent nor has it provided unequivocal support for this purported inverse relationship. This study investigated the effect of dietary folate on N-methyl-N-nitrosourea (MNU)-induced mammary tumorigenesis in rats. Weanling, female Sprague-Dawley rats were fed diets containing either 0 (deficient; n = 22), 2 (basal dietary requirement, control; n = 20) or 8 mg (supplemented; n = 20) folate/kg diet for 30 weeks. At 50 days of age, rats received an i.p. injection of MNU (50 mg/kg body wt). At necropsy, all macroscopic mammary tumors were identified and examined microscopically. The effect of dietary folate on genomic DNA methylation in mammary tumorigenesis was determined by the in vitro methyl acceptance assay. The incidence of mammary adenoma and adenocarcinoma in the folate-deficient group was lower than that of the control and folate-supplemented groups (55 versus 90 and 75%, respectively, P = 0.043). Kaplan-Meier analyses also demonstrated a similar trend in the rates of appearance of either adenoma or adenocarcinoma (P = 0.06). In contrast, folate supplementation did not significantly modulate mammary tumorigenesis compared with the control group. Although mammary tumors were significantly hypomethylated compared with non-neoplastic mammary tissues in each dietary group (P < 0.03), folate status did not significantly affect the extent of DNA methylation. The data suggest that dietary folate deficiency of a moderate degree suppresses, whereas folate supplementation at four times the basal dietary requirement does not significantly modulate, mammary tumorigenesis in this model. The role of folate in mammary tumorigenesis needs to be clarified for safe and effective prevention of breast cancer.